Department of Endocrinology, Mater Misericordiae University Hospital, Dublin, Ireland.
Diabetes Metab. 2011 Dec;37(6):512-9. doi: 10.1016/j.diabet.2011.04.002. Epub 2011 Jun 16.
The prevalence of hepatocyte nuclear factor (HNF)-1A and HNF4A mutations, and the clinical implications following the genetic diagnosis of maturity-onset diabetes of the young (MODY) in the Irish population, remain unknown. The aim of this study was to establish the occurrence of HNF1A and HNF4A mutations in subjects classified clinically as MODY to identify novel mutations, and to determine the phenotypic features and response to therapy.
A total of 36 unrelated index cases with a clinical diagnosis of MODY were analyzed for HNF1A/HNF4A mutations. OGTT was performed to determine the degree of glucose tolerance and insulin secretory response. Also, 38 relatives underwent OGTT and were tested for the relevant known mutations. HNF1A-/HNF4A-MODY subjects were compared with nine HNF1A mutation-negative relatives and 20 type 2 diabetic (T2DM) patients.
Seven different HNF1A mutations were identified in 11/36 (30.5%) index cases, two of which were novel (S352fsdelG and F426X), as well as two novel HNF4A mutations (M1? and R290C; 6%). Family screening revealed 20 subjects with HNF1A and seven with HNF4A mutations. Only 51.6% of HNF1A mutation carriers were diagnosed with diabetes by age 25 years; 11 of the mutation carriers were overweight and four were obese. Insulin secretory response to glucose was significantly lower in HNF1A-MODY subjects than in T2DM patients and HNF1A mutation-negative relatives (P=0.01). Therapeutic changes occurred in 48% of mutation carriers following genetic diagnosis.
There was an HNF1A-MODY pick-up rate of 30.5% and an HNF4A-MODY pick-up rate of 6% in Irish MODY families. Genetically confirmed MODY has significant therapeutic implications.
在爱尔兰人群中，成熟型糖尿病（MODY）患者的肝细胞核因子（HNF）-1A 和 HNF4A 突变的流行率以及遗传诊断后的临床意义尚不清楚。本研究旨在确定临床上被归类为 MODY 的患者中 HNF1A 和 HNF4A 突变的发生情况，以鉴定新的突变，并确定表型特征和治疗反应。
共分析了 36 例临床诊断为 MODY 的非相关指数病例，以分析 HNF1A/HNF4A 突变。进行 OGTT 以确定葡萄糖耐量和胰岛素分泌反应程度。此外，38 名亲属接受了 OGTT 并接受了相关已知突变的检测。将 HNF1A-/HNF4A-MODY 受试者与 9 名 HNF1A 突变阴性的亲属和 20 名 2 型糖尿病（T2DM）患者进行比较。
在 36 例指数病例中发现了 7 种不同的 HNF1A 突变，其中 2 种为新突变（S352fsdelG 和 F426X），以及 2 种新的 HNF4A 突变（M1?和 R290C；6%）。家族筛查显示 20 名 HNF1A 和 7 名 HNF4A 突变携带者。只有 51.6%的 HNF1A 突变携带者在 25 岁之前被诊断为糖尿病；11 名突变携带者超重，4 名肥胖。HNF1A-MODY 受试者的葡萄糖刺激胰岛素分泌反应明显低于 T2DM 患者和 HNF1A 突变阴性的亲属（P=0.01）。遗传诊断后，48%的突变携带者发生了治疗变化。
在爱尔兰 MODY 家族中，HNF1A-MODY 的检出率为 30.5%，HNF4A-MODY 的检出率为 6%。经基因证实的 MODY 具有重要的治疗意义。
